Targeting Egr-1 with Curcumin Analogs for Prostate Cancer Prevention Bisoffi, Marco Project Summary The problem addressed in this proposal: Field cancerization, i.e. the presence of genetic and biochemical abnormalities in histologically normal tissues outside the tumor margins, may indicate a status of pre- malignancy in prostatic tissues that set the stage for tumor development. By definition, detectable molecular alterations in these tissues can represent early biomarkers of disease, even before disease is manifested histologically and long before a clinical problem arises. In addition, some of these changes, because of their early appearance, might be clinically useful targets for prevention, such as for example by dietary ingredients. While this concept has long been recognized for prominent compounds, such as from green tea (Epigallocatechin-3-gallate), tomatoes (Lycopene), grapes (Resveratrol), and Turmeric (Curcumin), the identification of the underlying mechanisms still awaits elucidation. Description of the investigation: We have identified an elevated expression of the transcription factor early growth response protein 1 (Egr-1) in tumor adjacent histologically normal prostatic tissues through gene array analysis, and confirmed our initial observation by reverse transcriptase polymerase chain reaction. We hypothesize that Egr-1 expression is not only indicative of prostatic field cancerization, but also represents a suitable target for defining new preventive strategies. We have assembled a multidisciplinary team of basic and clinical researchers to address the two following Specific Aims: Aim 1: Determine the expression of Egr-1 in pre-malignant, disease-free prostatic tissues. This will answer the question of whether Egr-1 expression is elevated in prostatic tissue at risk of tumor initiation. Aim 2: Identify lead compounds of Curcumin analogs inhibitory for Egr-1 expression. This will answer the question of whether Egr-1 expression can be regulated by natural dietary products. Importance of the investigation: Population based epidemiological studies indicate that dietary ingredients and natural products act as preventive agents such as Curcumin for prostate cancer. However, the underlying mechanisms are not known in most of the cases. A detailed understanding of these mechanisms is of utmost importance, as it will identify suitable targets and provide avenues towards the development of specific and directed prevention strategies. The present proposal contributes to the development of more effective strategies for prostate cancer prevention, thereby addressing the annual incidence rate of approximately 220,000 men in the United States alone. Targeting Egr-1 with Curcumin Analogs for Prostate Cancer Prevention Bisoffi, Marco Project Narrative The first phase of our project is designed to test the validity of a molecule termed Egr-1 that we found abnormally expressed in prostatic tissues adjacent to tumors. We hypothesize that abnormal Egr-1 expression indicates pre-malignancy and sets the stage for tumor development. In the second phase, we will identify analog compounds of the natural product Curcumin (found in Indian spices, such as Turmeric, Curry) that are capable of inhibiting Egr-1 expression. We expect that such novel and potent compounds will ultimately lead to clinical trials for prostate cancer prevention using dietary supplements.